Project Summary Despite enormous expenditures and efforts by academic, government, and pharmaceutical institutions, most drugs that show promise against human breast cancer in preclinical testing in mice, fail to cure breast cancer in the clinic. There is a great need for improved drug response-predictive testing of human breast cancer in the preclinical setting to identify the best drug candidates. Based on novel insight gained in our laboratories, as a key first step we propose to correct the mouse endocrine environment to more adequately mimic the endocrine environment of breast cancer patients. Novel and independent insight from the two collaborating laboratories suggest that prolactin acts as a modulator of drug sensitivity in human breast cancer. Prolactin receptors are expressed, often at elevated levels, in a majority of human breast cancers. However, current mouse models are inadequate since mouse prolactin prevents activation of human prolactin receptors. Thus, current predictive testing of drugs against human breast cancer is performed on human breast cancer lines selected for growth under prolactin-free conditions. We will now test the role of prolactin as a modulator of breast cancer drug sensitivity and biology. For this study, a mouse model that expresses physiological levels of human prolactin has been genetically engineered for more accurate predictive testing of drugs on human breast cancer xenotransplants. The central hypothesis is that PRL receptor signaling, through its effects on mammary cell survival, growth, and differentiation, modulates sensitivity of breast cancer cells to anti-tumor agents. Consistent with this, we further hypothesize that mice, in which endogenous mouse prolactin has been replaced with physiological levels of human prolactin, will restore prolactin receptor signaling in human breast cancer xenotransplants and provide a more relevant endocrine environment for improved prediction of clinical responsiveness of breast cancer to therapeutic agents. Finally, we hypothesize that the hPRL expressing mice will allow us to establish new and transplantable breast cancer lines that more closely resemble primary breast human cancer than existing metastasis-derived tumor cell lines. If successful, the new mouse model would be available for testing of a broad number of human breast cancer drug candidates, with the potential for more reliable prediction of clinical efficacy. In addition, successful transplantation of primary breast cancer tissue with epithelial and stromal components will pave the road to a new personalized medicine approach to treatment of breast cancer patients. Project Narrative Most drugs that work when tested on human breast cancer in mice, fail to cure breast cancer in humans. There is a great need to improve the ability to predict whether candidate breast cancer drugs will work in patients. To this end, we have developed a new mouse model with a hormone environment that more closely resembles that of breast cancer patients. We will test the hypothesis that the new mouse represents an improved preclinical model for more accurate predictive testing of breast cancer drug candidates.